Sodium-glucose cotransporter 2 inhibitors (SGLT2i) use may reduce cardiac arrhythmia risk and should be considered for use in patients with diabetes mellitus (DM), heart failure (HF), and chronic kidney disease (CKD), according to findings published in Cardiovascular Diabetology, although additional research into the mechanisms of SGLT2i is needed.
In patients with HF, DM, and CKD, cardiac arrhythmias are linked to poorer outcomes, according to researchers. SGLT2is inhibit sodium and glucose reabsorption within the proximal tubules of the kidney, with canagliflozin, dapagliflozin, and empagliflozin being the most commonly used medications in the class. Although the cardioprotective effects of these medications have been recognized in recent years, the associations found between SGLT2i and atrial fibrillation (AF) remain inconsistent. The current study was designed to assess the effects of SGLT2i treatment on common arrhythmia outcomes — AF, atrial flutter (AFL), cardiac arrest, and ventricular tachycardia (VT) — and the related complication of embolic stroke in patients with CKD, DM, and HF.
ClinicalTrials.gov, EMBASE, and MEDLINE were searched for randomized controlled trials from inception to August 2020 that randomly assigned patients with CKD, DM, and HF to SGLT2i or placebo. Outcomes included AF, embolic stroke, AFL, AF/AFL, VT, and cardiac arrest. A random-effects model was used to pool relative risks (RRs) and 95% CI. Out of the 4532 papers identified by the search, 22 trials and 52,115 total patients were ultimately included (29,211 on SGLT2i and 22,904 on placebo; mean age 63.2; 64.8% men). The median follow-up was 1.0 years (range 0.1-4.2).
The overall percentage of participants included with DM was 94.6%, 53.0% with CKD, and 21.4% with HF, and the mean percentage with a history of AF was 10.2% (range 5.5-70.9). Eleven trials had a low risk for bias, 6 trials had a high risk for bias, and 5 trials had an unclear risk for bias.
SGLT2i treatment was associated with an 18% lower risk for AF (RR, 0.82; 95% CI, 0.70-0.96; P =.94), and a 68% lower risk for embolic stroke (RR, 0.32; 95% CI, 0.12-0.85; P =.99), compared with placebo. With AF and AFL used as a composite endpoint, SGLT2i were associated with an 18% reduction in risk compared with placebo (RR, 0.82; 95% CI, 0.71-0.95; P =.90).
Compared with placebo, SGLT2i use was associated with a 27% reduction in VT risk (RR 0.73; 95% CI, 0.53-0.99; P =.61), while the AFL and cardiac arrest risk reductions did not reach statistical significance (RR 0.83; 95% CI, 0.68-1.17; and RR, 0.83; 95% CI, 0.61-1.14; respectively). These associations seemed to remain consistent across varying baseline conditions (atherosclerotic cardiovascular disease [ASCVD] vs no ASCVD; DM vs CKD vs HF), follow-up duration, and the SGLT2i used.
Sensitivity analyses that excluded studies with high or unclear bias risk yielded similar results, as did using odds ratio as an effect measure. No significant subgroup differences were found when trials were stratified according to DM compared with other conditions.
There are some limitations. The included trials did not include arrhythmia as the prespecified outcomes, meaning that there could be ascertainment bias, nor did the trials have adjudicated outcomes, which could lead to incomplete and inaccurate data.
Despite the limitations, study investigators concluded through meta-analysis “that SGLT2i reduced the risk for AF and VT.” They indicated, “Our study provides further robust evidence for recommending the use of SGLT2i in patients with DM, CKD, and HF to reduce related cardiac complications and comorbidities. However, the mechanisms by which SGLT2i protects against arrhythmias are complex and further research is warranted.”
Li HL, Lip GH, Feng Q, et al. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and cardiac arrhythmias: a systematic review and meta-analysis [published online May 7, 2021]. Cardiovasc Diabetol. doi: 10.1186/s12933-021-01293-8